Project Summary Radiation therapy is a major component constituting the standard of care in glioblastoma. Despite advances in the focused delivery of radiation, life expectancy for glioblastoma has changed little in recent years. An emerging technique to enhance the efficacy of applied radiation is the introduction of atoms with large atomic numbers within tumor cells prior to radiotherapy. The physical basis for this technique lies in the favorable photoelectric absorption coefficients of atoms with large atomic numbers; compared to the atoms composing the soft tissue of the body, larger atoms with higher atomic numbers are more likely to interact with incident ionizing radiation and emit electrons. These free radical electrons promote the generation of reactive oxygen species, which cause damage to DNA and cellular structures in their immediate vicinity, resulting in cell death. The advent of targeted nanoparticle therapeutics has resulted in an improved ability to accurately deposit nanoscale metal clusters at subcellular sites of interest. Nanoparticles can be aimed at molecular epitopes expressed by glioblastoma cells. Instead of ferrying a drug to tumor regions, metal-core nanoparticles themselves become therapeutic agents in so-called nanoparticle-mediated deposition of radiation (NMDR). Prior investigations into nanoparticle-mediated deposition of radiation have been conducted using gold and other heavy-metal based technologies which are hindered by their limited biocompatibility and biodegradability. Conversely, iron oxide nanoparticles possess distinct benefits over other metal-core nanoparticles, including approval by the U.S. Food and Drug Administration, known biocompatibility and excretion profiles in humans, and superparamagnetism that allows for visualization in magnetic resonance imaging. This proposal describes the evaluation of iron oxide nanoparticles to enhance the efficacy of radiotherapy in glioblastoma. The Specific Aims of the proposed research are to (1) evaluate the effect of core size on NMDR, (2) asses the effect of polymer coating on NMDR, and (3) investigate the efficacy of glioblastoma tumor targeting for iron oxide NMDR. These aims will be achieved by interrogating nanoparticle design parameters, including core size and surface coating on reactive oxygen species production upon exposure to ?-ray radiotherapy. Furthermore, an iron oxide nanoparticle will be created through conjugation with the tumor-targeting peptide chlorotoxin. The efficacy of this nanoparticle will be evaluated in mice bearing orthotopic human primary glioblastoma xenografts. These Specific Aims will provide crucial knowledge regarding the potential for a clinically-relevant radiosensitizer as applied towards the treatment of the most common malignant human brain tumor. In the long-term, iron oxide nanoparticles may improve survival outcomes for many forms of cancer if they can be applied as radiosensitizers.!